tbuckley/cabot-search huggingface dataset:
Liquid biopsy effectiveness of esophageal cancer-related genes and their correlation in clinical research.
Authors: Bo Jiang, Yangui Lin, Hongliang Hui, Huaming Li, Yujun Zhou, Yaru Chen, Weishuang Zhang, Shaochen Cheng, Yiqian Zhang
Journal: Journal of Clinical Oncology (2023)

e16004 Background: Esophageal cancer ranks as the sixth most common cause of cancer-related deaths worldwide. The occurrence and development of esophageal cancer is a complex process that involves multiple genetic variants, including changes in gene function, which could be a crucial factor in its development. Hence, studying the molecular genetic changes specific to esophageal cancer is essential for understanding its mechanism and guiding clinical treatment. In this study, we analyzed and documented genetic variations and clinical information of 82 esophageal cancer patients to provide new insights into the correlation between genes and clinical symptoms. Methods: The tissue and blood-based DNA samples from 82 patients were analyzed using 680-gene targeted capture sequencing for CNV, fusion, SNV, indel, MSI, and TMB. Coverage of tissue with 2200X, cfDNA 20000X, and control gDNA 10000X. Additionally, the level of PD-L1 expression was assessed in the tissue samples. TMB was classified as TMB-H ( &gt; 10 mutations/megabase) and TMB-L ( &lt; 10). MSI-H was determined with instability ≥20% of 117 sites for detection, while &lt; 20% was determined as MSS. Results: The analysis revealed 786 SNV/indel mutations in 82 patients, of which 346 (44.02%) mutations were detected in both tissue and plasma, 296 (37.66%) only found in tissue, and 144 (18.32%) only found in plasma. 378 mutations were detected in CNV, with 181 mutations (47.88%) in tissue and blood, 186 mutations only found in tissue (49.21%), and 11 mutations only in plasma (2.91%). The high-frequency mutation genes identified in this study were TP53, CCND1, FGF19, FGF3/4, NOTCH1, and PIK3CA, which are also listed as high frequency mutated genes in the IntoGen database (7 cohorts, 945 samples). However, the genes CCND1, FGF19, FGF3/4, and PIK3CA in the CNV results were not in the IntoGen high frequency mutated gene list. The results of tTMB vs bTMB were consistent in 80 out of 82 patients (97.56%). Among the 82 samples, 79 had low expression of PD-L1, while 3 had high PD-L1 expression and TMB-L, MSS. Conclusions: Fibroblast growth factor (FGF) signaling system may plays an important role in tumorigenesis and progression. Increase in the expression of FGFs and fibroblast growth factor receptor genes, might lead to genetic alterations in their protein structures and activation of the FGFs-FGFR signaling pathway, which may contribute to the onset of esophageal cancer. In conclusion, the results of our study suggest that the detection of tissue mutations in the blood of esophageal cancer patients is challenging and cannot be reliably determined by a single blood sample. The incidence of PD-L1 expression was low in all esophageal cancer tissues. Further investigation into the correlation between CCND1, FGF19, FGF3/4, and PIK3CA genes and esophageal cancer is warranted.
Genomic characterization in gastrointestinal cancer patients based on cfDNA sequencing.
Authors: Minghua Wang, Zhi Zheng, Zhouyang Wang, Shaochen Cheng, Yaru Chen, Yuanyuan Liu, Xiaojing Ren
Journal: Journal of Clinical Oncology (2023)

e15507 Background: Gastrointestinal cancer (GIC) is one of the most prevalent cancers worldwide. Late stages diagnosis is one of the main reasons for poor prognosis of GIC. The invasive nature of endoscopy assay has greatly decrease the willingness for early screening, nearly 50% of patients diagnosed with GIC were in advanced stages. With the advanced of next-generation sequencing (NGS) technology, liquid biopsy has quickly gaining interest in early cancer screening. In order to address the poor prognosis of GIC, mutation features and potential biomarkers were investigated using NGS data from 169 Chinese GIC patients with blood derived cell-free DNA (cfDNA). Methods: Blood-derived cfDNA sampels were collected from Chinese patients with colorectal cancer (CRC) (n = 121) and gastric cancer (GC) (n = 48) and then performed pan-cancer sequencing panel targeting 680 cancer-related genes. Genomic alterations of single nucleotide variations, short indels and tumor mutation burden were analyzed. Two-sided Fisher’s exact test was used for all statistical analyses. COSMIC data was retrieved from COSMIC database version 97. Results: Among GC patients, the proportion of patients possessing mutations in TP53 (43.75% vs 37%, p = 0.49) and KRAS (10.42% vs 5.6%, p = 0.19) showed consistent distribution with COSMIC database. While KIT (14.58% vs 3.42%, p = 0.0014) and SYNE1 (10.42% vs 30.8%, p = 0.0021) showed varied distribution outcomes. CRC patient cohort also showed coherent distribution compared with COSMIC database. No significant difference was detected between the two cohorts in TP53 (51.5% vs 44.57%, p = 0.085), KRAS (36.53% vs 32.33%, p = 0.24), APC (44.91% vs 47.74%, p = 0.48) and PIK3CA (14.37% vs 14.10%, p = 0.91). However, the proportion of SYNE1 mutation is still significantly lower than in the COSMIC database (17.37% vs 29.31%, p = 0.0006). As all patients from the study cohort are Chinese, whether a lowered occurrence of SYNE1 mutation is specific to Chinese or certain region can be further studied. Conclusions: This study revealed that the mutational landscape of liquid biopsy cfDNA sequencing is highly consistent with existing database, which has consolidated the feasibility of liquid biopsy in early cancer detection. Besides, this study also revealed a lowered occurrence of SYNE1 and increased KIT mutation in the cohort. While increased KIT mutation can be explained by the proportion of recruited gastrointestinal stromal tumor patients, the lowered SYNE1 can provide new insights into region-specific diagnosis and treatment selection.
Homologous recombination-related (HRR) gene mutation profiling and the association with TMB in Chinese patients with esophageal and gastric cancer.
Authors: Da Wang, Huan Yi, Yangyang Yu, Mingzhe Xiao, Chuang Qi
Journal: Journal of Clinical Oncology (2023)

e16000 Background: Homologous recombination deficiency (HRD) is associated with tumorigenesis and could predict the response of PARP inhibitor (PARPi) therapy and immunotherapy. Loss of function or deleterious mutations in homologous recombination-related (HRR) genes contribute to HRD phenotype. Methods: Tumor tissue samples from 1237 Chinese patients with esophageal and gastric cancer were sequenced with 551 cancer-related genes. Based on the clinical evidence, 15 HRR genes ( ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, PPP2R2A) were selected. 623 patients with WES data from the TCGA datasets were included for analysis. Results: In the Chinese cohort, 25.1% (62/247) esophageal cancer (EC) patients and 20.71% (205/990) gastric cancer (GC) patients exhibited somatic HRR (sHRR) gene mutations. The most frequently mutated genes were CHEK2 (7%) in EC and ATM (8%) in GC. The germline HRR (gHRR) gene mutations were identified in 48.16% (118/245) EC patients and 50.66% (498/983) GC patients. BRCA2 was the most common mutant gene (22% in EC and 9% in GC). 4.84% EC patients and 4.14% GC patients carried both germline and somatic HRR gene mutations. The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (EC, 8.09 vs 4.41, p &lt; 0.001; GC, 8.09 vs 4.26, p &lt; 0.001). However, the median TMB was similar between the gHRR-Mut and the gHRR-WT patients (EC, 5.67 vs 5.67, p = 0.903; GC, 4.96 vs 4.41, p = 0.356). In the TCGA cohort, 15.68% (29/185) EC patients and 23.97% (105/438) GC patients exhibited sHRR gene mutations. The most common mutant gene was ATM (5% in EC and 10% in GC). The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (EC, 4.78 vs 2.75, p &lt; 0.001; GC, 21.23 vs 2.65, p &lt; 0.001). For the TCGA gastric cancer cohort, the patients with sHRR-Mut had a significantly better median overall survival compared to the ones with sHRR-WT (46.9 months vs 26.5 months, p = 0.043). Conclusions: Our data reported the genetic landscape of HRR genes in Chinese esophageal and gastric cancer patients. Patients with somatic HRR gene mutations had a significantly elevated TMB level. In gastric cancer, patients carried somatic HRR gene mutations had a significantly prolonged OS.
Use of germline testing in patients with prostate, pancreatic, or ovarian cancer in Washington (WA) state.
Authors: Qin Sun, Veena Shankaran, Catherine R. Fedorenko, Karma L. Kreizenbeck, Scott David Ramsey
Journal: Journal of Clinical Oncology (2023)

6572 Background: Germline genetic mutations are seen in approximately 10-15% of patients with prostate, pancreatic, and ovarian cancer. While universal germline testing is recommended for patients with these cancers to inform both familial risk and therapeutic approach, underutilization of germline testing has been reported. We investigated the rates of and factors associated with germline testing in a population-based sample of patients with prostate, pancreatic, and ovarian cancer in WA state. Methods: We linked Washington state cancer registry records from 2017-2019 with claims records for two large commercial insurers, Medicare, and Medicaid. Patients with prostate (metastatic, regional node-positive, or high-risk localized), pancreatic, and ovarian (including fallopian tube and peritoneum) cancer who were diagnosed in 2017-2019 were identified. Using claims from this database, we identified patients who received germline testing in the first two years of diagnosis. We excluded those who were not continuously enrolled in a health plan during the testing period of interest or died within 3 months of diagnosis. We used a multivariate logistic regression model to investigate factors associated with germline testing. Results: Among 2,077 patients, 429 (20.7%) received germline testing. Testing rates were 6.3% (53 of 842 patients) in prostate cancer, 15.4% (118 of 765 patients) in pancreas cancer, and to 54.9% (258 of 470 patients) in ovarian cancer; median time to testing for prostate, pancreas, and ovarian cancer was 162, 133, and 64 days respectively. Testing rates were higher in later years, in patients with more advanced stage cancers and lower in Asian patients and patients with more comorbid conditions. Conclusions: Despite guideline recommendations, germline testing rates are low among cancer patients in WA state, with the lowest rates in prostate cancer patients and in Asian and higher comorbidity populations. Underutilization of germline testing may not only adversely affect treatment, but also represents a missed opportunity for testing of high-risk families. Further studies should identify and address barriers to germline testing in high-risk populations. [Table: see text]
Neoadjuvant T-VEC + nivolumab combination therapy for resectable early metastatic (stage IIIB/C/D-IV M1a) melanoma with injectable disease: NIVEC trial.
Authors: Lisanne P. Zijlker, Winan J. van Houdt, Emma H.A. Stahlie, Viola Franke, Maartje W. Rohaan, Antonios Delatzakis, Charlotte Zuur, Willem M.C. Klop, Bart A. van de Wiel, Anke Kuijpers, Elianne de Boer, Johannes V. van Thienen, John B. A. G. Haanen, Alexander Christopher Jonathan Van Akkooi
Journal: Journal of Clinical Oncology (2023)

9546 Background: Neoadjuvant systemic treatment with checkpoint inhibitors (ICI) has shown high response rates in patients with resectable metastasized melanoma. In patients with unresectable stage IIIB-IVA melanoma, intralesional treatment with talimogene laherparepvec (T-VEC) has also shown high and durable response rates. In this trial we investigated the safety and efficacy of neoadjuvant treatment with a combination of nivolumab and T-VEC in regionally metastasized melanoma. Methods: In this single arm phase II open-label trial (NCT04330430), 24 patients with resectable stage IIIB-IVA melanoma were included. Inclusion criteria were a RECIST 1.1 measurable lesion of ≥10mm and no prior systemic therapy. Treatment consisted of four doses of intralesional T-VEC (dose in ml according to the size of the lesions) and three doses of nivolumab 240 mg flat dose every two weeks, followed by surgery. The primary endpoint was pathological response rate according to the International Neoadjuvant Melanoma Consortium (INMC) criteria, secondary endpoints were delay or failure to perform surgery, event free survival (EFS) from time of randomization and safety. Results: Baseline characteristics are presented in the table. The overall pathological response rate was 74%, with a major pathological response (MPR = pathologic complete response (pCR) + near-pCR (max 10% viable tumor cells) in 15 patients (65%), a partial response in two patients (9%), a non-response in 4 patients (17%) and progression of disease (PD) in two patients (9%). In one patient the response was not evaluable because surgery was delayed due to a vena cava thrombosis. The two patients with PD had evidence of distant metastasis on preoperative imaging and therefore did not proceed to surgery as planned. Grade 2 treatment related adverse events (trAE) occurred in 7 patients (29%) and grade 3 in 2 (8%). There were no grade 4-5 trAEs. The 1-year EFS was 75% (95%CI 0.55-1). Conclusions: Neoadjuvant combination therapy of nivolumab and T-VEC for patients with regionally metastasized melanoma (satellite/in-transit +/- lymph node metastases) has an acceptable toxicity profile and has shown a significant major pathological response rate of 65%. Clinical trial information: NCT04330430 . [Table: see text]
Homologous recombination deficiency (HRD) in non-small cell lung cancer: Genomic analysis using an RNA-based HRD algorithm.
Authors: Stephanie Thiede, Matthew Berginski, Akash Mitra, Timothy J. Taxter, Michelle M. Stein, Rotem Ben-Shachar, Halla Nimeiri, Charu Aggarwal, Jyoti D. Patel
Journal: Journal of Clinical Oncology (2023)

3123 Background: Recent evidence has suggested that some patients with non-small cell lung cancer (NSCLC) harbor a HRD signature that represents a distinct genomic subtype that could be targeted by PARP inhibitors (PARPi). However, there is little data on HRD prevalence in NSCLC or its genomic associations. Here, we evaluated the co-occurrence of driver mutations and established immune biomarkers with an RNA-based HRD signature in a large, real-world NSCLC cohort. Methods: We analyzed data from 5119 NSCLC patients that underwent sequencing via the Tempus xT test (DNA-seq of 648 genes; RNA-seq with whole exome capture). HRD status was predicted by the Tempus HRD-RNA test, a pan-cancer logistic regression classifier that uses an RNA gene expression signature optimized to distinguish between BRCA-biallelic loss and homologous recombination repair (HRR)-WT samples (Leibowitz et al, 2022). Cohort samples were excluded from model training. All comparisons were tested via chi-squared or Fisher’s exact tests. Results: An RNA-derived signature of HRD (HRD-RNA+) was observed in 3.53% (n=181/5119) of patients. HRD-RNA+ prevalence was higher in squamous cell carcinoma (84/1331, 6.3%) relative to adenocarcinoma (68/3015, 2.3%; p &lt; 0.001). The prevalence of select alterations by HRD-RNA status are shown in Table. Alterations in BRCA1/2 and HRR genes (inclusive of BRCA1/2) were enriched in HRD-RNA+ vs. HRD-RNA- cases (8.8% vs. 2.5%, p &lt; 0.001; 22% vs. 15%, p = 0.008 respectively). Notably, 141 (78%) HRD-RNA+ patients had no alterations in HRR genes. Of all NCCN targetable driver mutations assessed, KRAS G12C and ALK fusions were the only targetable drivers with significantly different prevalence in HRD-RNA+ vs. HRD-RNA- patients. Across the entire cohort, NCCN driver mutations were depleted in HRD RNA+ patients (18% in HRD-RNA+ vs. 30% in HRD-RNA-, p &lt; 0.001). Immune biomarkers (TMB, PD-L1) did not vary by HRD-RNA status. Conclusions: Compared to HRD-RNA- NSCLC, HRD-RNA+ NSCLC represents a unique, molecularly defined subset that has a decreased prevalence of NCCN-driver mutations and is not enriched for TMB-H or PD-L1 expression. Further, this signature increases the number of patients classified as HRD-RNA+ compared to HRR gene alterations alone. Functional characterization (e.g. RAD51 foci immunofluorescence assay) and clinical benefit of targeted HRD therapies such as PARPi should be explored in this HRD-RNA+ population. [Table: see text]
Adjuvant systemic chemotherapy with or without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastases resection (HARVEST): A prospective, randomized controlled trial.
Authors: Yu-hong Li, De-Shen Wang, Yang-Kui Gu, Lei Wen, Chao Ren, Xiao-Jun Wu, Yun-Fei Yuan, Bin-Kui Li, Yun Zheng, Pei-Rong Ding, Zhi-Qiang Wang, Zhi-Zhong Pan, Gong Chen, Li-Ren Li, Zhen-Hai Lu, Qiong Tan, De-Sen Wan, Rui-Hua Xu
Journal: Journal of Clinical Oncology (2023)

3516 Background: Several retrospective studies have previously demonstrated that a combination of adjuvant systemic chemotherapy and hepatic arterial infusion (HAI) could benefit patients following colorectal cancer liver metastases (CRLM) resection. This prospective clinical study aimed to determine whether adding HAI to adjuvant systemic chemotherapy could reduce the risk of recurrence following CRLM resection. Methods: The HARVEST study is an investigator-initiated, prospective, randomized controlled trial investigating the efficacy and safety of adjuvant intravenous chemotherapy with or without HAI floxuridine (FUDR) in CRLM patients that underwent liver metastasectomy. Patients in the systemic chemotherapy plus HAIC arm (HAI group) received systemic FOLFOX (q2w) plus HAI (FUDR, d1-14, q4w) for up to 6 months, while the systemic chemotherapy group without HAI (non-HAI group) received intravenous FOLFOX only. The primary study endpoint is the relapse-free survival in the modified intention-to-treat (mITT) population. Blood samples at different time points were also collected and circulating tumor DNA (ctDNA) was tested for NPY and SEPT9 methylation. Results: The study was prematurely terminated due to FUDR production halt in China. Ninety-two patients were randomized and seventy-seven patients (38 in the HAI group and 39 in the non-HAI group) were eventually included in our mITT analysis. After a median follow-up of 35.8 months, there were 22 (57.9%) and 25 (64.1%) recurrences in the HAI and non-HAI groups, respectively. The median relapse-free survival was 20.0 months in the HAI group and 11.7 months in the non-HAI group (p = 0.14; HR 0.65; 95% confidence interval [CI] 0.37 to 1.16). No significant difference was found in terms of overall survival between the two groups (p = 0.461). Our subgroup analysis revealed that patients with multiple liver metastases (p &lt; 0.01) and RAS/BRAF mutation (p &lt; 0.01) could benefit from adjuvant HAI treatment. Based on ctDNA status, patients with positive postoperative ctDNA methylation benefited from adjuvant HAI treatment (p &lt; 0.01), while those with negative postoperative ctDNA methylation status (p = 0.95) did not. Chemotherapy-related adverse events were comparable between the two groups. Conclusions: Adjuvant chemotherapy intensification using HAI did not significantly reduce recurrence following CRLM resection. However, patients with multiple liver metastases, RAS/BRAF mutation and those with positive postoperative ctDNA might benefit from adjuvant HAI treatment. Clinical trial information: NCT03500874 .
Colorectal cancer mortality in young adults in the United States.
Authors: Alexander Didier, Danae M. Hamouda, Jeffrey M. Sutton
Journal: Journal of Clinical Oncology (2023)

e15530 Background: Colorectal cancer (CRC) is typically considered a disease that affects older adults. However, recently a concerning increase in the incidence rates of CRC among young adults (age &lt; 50) has been noted. Given the limited analysis of colorectal cancer mortality assessing for age-based differences, we aimed to characterize trends in mortality rates of CRC between 1999 and 2020 in the United States, with the hypothesis that younger patients would also experience an increasing morality rate from CRC in concert with the increasing incidence. Methods: We queried the Centers for Disease Control database for mortality statistics with an underlying cause of death of colon and rectal cancer between the years 1999 - 2020. Crude mortality rates (CMR) were calculated per 100,000 deaths. Patients were stratified based on early-onset (30-49 years), average-onset (50-69 years), and late-onset (70+ years) CRC. For each cohort, we examined race and U.S. Census Region variables to assess drivers in mortality. Temporal trends were assessed using Joinpoint regression software. Average annual percent change (AAPC) were considered statistically significant if p &lt; 0.05. Results: Between 1999 and 2020, 1,166,158 deaths due to CRC occurred and the CMR decreased from 20.3 to 15.7. For patients aged &gt; 70, colorectal cancer mortality rate decreased from 148.6 to 75.9 at an average of 3.2% annually during this time frame. For the group aged 50-69, there was a decrease in CMR from 32.7 to 24.2, reflecting an average annual decrease of1.4%. In patients aged 30-49, CMR increased from 3.6 to 4.2, reflecting an average annual percent increase in mortality of 0.7%. This increase in CRC mortality in the youngest cohort occurred independent of geographical location. Mortality in young adults increased the fastest in the West at a rate of 1.1% annually and slowest in the South at 0.4% annually. Similar increases in mortality rates were identified when cohorts were stratified by race, with Non-Hispanic American Indian/Native American populations experiencing the most rapid increases in mortality at 3.4% annually. Conclusions: These results demonstrate age-related disparities in recent CRC mortality trends. While the overall mortality of CRC has decreased over the last two decades, this decrease was largely due to declining mortality in older adults. In contrast, younger adults experienced a sharp rise in CRC mortality rates, increasing at an average annual percentage increase of almost 1% each year independent of racial or geographic factors. These results highlight a concerning emerging trend with significant public health implications and provide rationale for increased surveillance in young adults.